Objectives To assess efficacy, pharmacokinetics (PK) and safety of intravenous (i.v.) golimumab i... more Objectives To assess efficacy, pharmacokinetics (PK) and safety of intravenous (i.v.) golimumab in patients with polyarticular-course JIA (pc-JIA). Methods Children aged 2 to <18 years with active pc-JIA despite MTX therapy for ≥2 months received 80 mg/m2 golimumab at weeks 0, 4, then every 8 weeks through week 52 plus MTX weekly through week 28. The primary and major secondary endpoints were PK exposure and model-predicted steady-state area under the curve (AUCss) over an 8-week dosing interval at weeks 28 and 52, respectively. JIA ACR response and safety were also assessed. Results In total, 127 children were treated with i.v. golimumab. JIA ACR 30, 50, 70, and 90 response rates were 84%, 80%, 70% and 47%, respectively, at week 28 and were maintained through week 52. Golimumab serum concentrations and AUCss were 0.40 µg/ml and 399 µg ⋅ day/ml at week 28. PK exposure was maintained at week 52. Steady-state trough golimumab concentrations and AUCss were consistent across age cate...
BackgroundSystemic Lupus erythematous (SLE) is a heterogenic clinical syndrome with a multifactor... more BackgroundSystemic Lupus erythematous (SLE) is a heterogenic clinical syndrome with a multifactorial etiology including diverse environmental, immunological and genetic causes and modifiers. Increasingly, utilizing next generation sequencing tooIs, monogenic forms of SLE have been identified.ObjectivesThe aim of our study was to identify monogenic causes of SLE in the unique pediatric population of Northern Israel.MethodsA retrospective and prospective study was carried out between 2010-2021 in a single tertiary pediatric medical center. Genetic testing including Whole exome sequencing (WES) was performed for select patients including family history of SLE, consanguinity and\or clinical findings suggestive of specific disorder.Results75 children were diagnosed with SLE. 13/75 had one or more relatives with SLE, including a pedigree with 4 affected members. Mean age at presentation was 10.1±4.7. A monogenic disorder was identified in total of 7/75 of pedigrees. Four patients were dia...
Pediatric Infectious Disease Journal, May 26, 2020
Pediatric inflammatory multisystem syndromes associated with Severe Acute Respiratory Syndrome Co... more Pediatric inflammatory multisystem syndromes associated with Severe Acute Respiratory Syndrome Coronavirus 2 are emerging in recent reports. We describe a patient with critical illness consistent with atypical Kawasaki disease with cardiac dysfunction and abdominal involvement presenting weeks after Severe Acute Respiratory Syndrome Coronavirus 2 infection. Our patient showed unique central nervous system involvement with small vessel vasculitis and profound hypocomplementemia, both not previously reported in case descriptions and may hint at possible disease mechanisms.
Objectives Takayasu arteritis (TAK) is a large-vessel vasculitis rarely reported in children and ... more Objectives Takayasu arteritis (TAK) is a large-vessel vasculitis rarely reported in children and infants. Most articles on paediatric TAK have not focused on infants. We present the largest case series of infantile TAK, aiming to identify its demographic and clinical characteristics and compare them with existing data on older children. Methods We conducted an international multicentre retrospective cohort study. Epidemiological and clinical data were collected from patients’ charts from six rheumatology centres. All patients met both the EULAR/PReS 2008 criteria and the 1990 ACR/EULAR criteria and were diagnosed with TAK at age &lt;5 years. Results Twelve patients were included (50% female). Median age of symptom onset was 11 months, with a diagnostic delay of 4 months. The most common symptoms at presentation were hypertension, blood pressure differences between limbs, and fever. The most commonly involved arteries were the abdominal aorta and renal artery. Medications included steroids, conventional and biologic DMARDs, and other immunosuppressive therapies. Half of the patients received biologic agents, of which infliximab had the highest complete remission rate (40%). Other medications resulting in complete remission were CYC (40%) and MTX (38%). Invasive procedures were required for 58% of patients. The most common complications were cardiac (50%), stroke (42%), and serious infections (33%). No patients died. Conclusion This study presents the largest series of infantile TAK. Compared with other reported series on older children, infants with TAK have more severe disease and were more likely to receive biologic agents, develop complications, and require invasive interventions.
Background Familial Mediterranean fever (FMF) is the most common hereditary autoinflammatory synd... more Background Familial Mediterranean fever (FMF) is the most common hereditary autoinflammatory syndrome, affecting > 100,000 people. FMF is caused by mutations in the MEFV gene, which encodes for the pyrin protein that is part of the inflammation complex that activates IL-1β. Evidence from case reports/series and one controlled study support IL-1 blockage as a potential treatment for FMF. Canakinumab (CAN) is a selective fully human monoclonal anti-IL-1β antibody approved in the EU and US for the treatment of cryopyrin associated periodic syndrome (CAPS). Objectives This study served as a proof of concept to evaluate the role of CAN in the treatment of pediatric colchicine resistant (CR)-FMF. Methods This was a 2-center open-label, single-arm study. The population consisted of CR FMF patients (pts) 4-20 years of age, with a history of at least 3 documented FMF attacks in the 3 months prior to enrollment. Pts entered a 30-day run-in period (RI) during which FMF attacks were documented in a diary. Pts who experienced an investigator-confirmed FMF attack during RI were eligible to enter the treatment phase and receive a SC injection of CAN 2 mg/kg (max 150 mg) every 4 weeks for three times with the 1st dose given during an attack. The dose was doubled to 4 mg/kg (max 300 mg) if an attack occurred between Day 1 Baseline and Day 29 visits. Following the end of the treatment period, pts were followed until day 144 or until an attack occurred, whichever occurred first. Primary outcome was the proportion of pts with ≥50% reduction in FMF attack rate during the treatment vs. pretreatment period. Results Fifteen Israeli pts (9 males, 6 females) entered the RI period and 7 (median age 9.5 yrs; 6.8-14.9 yrs) all with CR FMF advanced to the treatment period. In total, 6/7 (86%) pts had a ≥50% reduction in their FMF attack rate during the treatment period. The median attack rate prior to CAN was 2.7 per 28 days, this decreased to 0.3 per 28 days during treatment, representing a median 89% reduction. Five mild and 3 moderate attacks were experienced by 4 pts (1 with 4 attacks, 1 with 2 attacks and 2 with 1 attack) during the treatment period; 2 pts had their CAN dose uptitrated. Investigators rated FMF control as very poor (n=3), poor (n=3) or fair (n=1) at baseline; this improved to good (n=3) /very good (n=4) for all pts during the treatment period. Elevated median baseline CRP and SAA normalized by Day 8, ESR by Day 28 and all remained normal for remainder of trial. Only 5/7 pts experienced an attack during follow up; the median time to attack following the last CAN dose was 25 days (3-34 days). In all, 11 adverse events (AEs) in 4 pts were reported after the first CAN dose; all were mild except for 2 moderate AEs (Strep infection, laceration), none led to medication discontinuation. Conclusions In this study of pediatric pts with colchicine resistant FMF, Canakinumab every 4 weeks substantially reduced the FMF attack rate consistent with that reported in adults. AEs were manageable. Further study is needed to better define the benefit of Canakinumab in FMF. Disclosure of Interest R. Brik: None Declared, Y. Butbul Aviel: None Declared, S. Lubin Employee of: Novartis, E. Ben Dayan Employee of: Novartis, L. Tseng Employee of: Novartis, P. Hashkes Grant/research support from: Novartis, Consultant for: Novartis, Speakers bureau: Novartis
Objectives: Behçet's disease (BD) is a variable vessel vasculitis. The most widely used classific... more Objectives: Behçet's disease (BD) is a variable vessel vasculitis. The most widely used classification criteria for adults is the International Behçet's Study Group (ISG) criteria. Recently, the paediatric BD (PEDBD) classification criteria has been developed for children. For disease activity, there are mainly two severity scores; the Iranian BD dynamic activity measure (IBDDAM) and BD current activity form (BDCAF). We tested the performances of PEDBD and ISG criteria and the correlation between severity scores and physician global assessment (PGA) in children with BD. Methods: Thirty BD patients from Hacettepe University, Ankara, Turkey; 24 from Erciyes University, Kayseri, Turkey; and 14 BD patients from Rambam Medical Centre, Haifa, Israel were included. As controls, children with systemic lupus erythematosus, polyarteritis nodosa, and Crohn disease from Turkey and Israel were included. The sensitivity and specificity of the PEDBD and ISG criteria were evaluated based on the features of the patients before or at 16 years of age. The gold standard for the diagnosis of BD was based on expert opinion at each centre. Expert PGA (visual analogue scale between 0-10; where 0 indicates no disease activity), IBDDAM, and BDCAF were evaluated at the time of diagnosis and at last follow-up in all patients. Results: Sixty-eight BD (disease onset≤16 years; 44.1% male) and 90 control patients were included. The sensitivity and specificity of PEDBD/ISG criteria were 73.5%/52.9% and 97.7%/100%, respectively. Thirty-two (47%) patients with BD failed to fulfill ISG criteria while almost all met PEDBD criteria. The median (interquartile range; IQR) IBDDAM and BDCAF scores at diagnosis were 6(4)/4(2); significantly decreased to 1(2)/1(2), respectively at latest follow-up (p<0.001 for both). The median (IQR) PGA score at diagnosis was 5(2); significantly decreased to 1(2) at latest follow-up (p<0.001). IBDDAM positively correlated with BDCAF (r=0.637; p<0.001). PGA positively correlated with BDCAF and IBDDAM (r=0.502; p<0.001 and r=0.624;p<0.001, respectively). Conclusions: In our study, the PEDBD criteria showed better sensitivity than ISG criteria which is a big advantage for paediatric patients for early diagnosis. We also demonstrated that the severity scores were positively correlated with each other and PGA; thus may be used in clinical practice for paediatric BD patients.
Objectives To assess efficacy, pharmacokinetics (PK) and safety of intravenous (i.v.) golimumab i... more Objectives To assess efficacy, pharmacokinetics (PK) and safety of intravenous (i.v.) golimumab in patients with polyarticular-course JIA (pc-JIA). Methods Children aged 2 to <18 years with active pc-JIA despite MTX therapy for ≥2 months received 80 mg/m2 golimumab at weeks 0, 4, then every 8 weeks through week 52 plus MTX weekly through week 28. The primary and major secondary endpoints were PK exposure and model-predicted steady-state area under the curve (AUCss) over an 8-week dosing interval at weeks 28 and 52, respectively. JIA ACR response and safety were also assessed. Results In total, 127 children were treated with i.v. golimumab. JIA ACR 30, 50, 70, and 90 response rates were 84%, 80%, 70% and 47%, respectively, at week 28 and were maintained through week 52. Golimumab serum concentrations and AUCss were 0.40 µg/ml and 399 µg ⋅ day/ml at week 28. PK exposure was maintained at week 52. Steady-state trough golimumab concentrations and AUCss were consistent across age cate...
BackgroundSystemic Lupus erythematous (SLE) is a heterogenic clinical syndrome with a multifactor... more BackgroundSystemic Lupus erythematous (SLE) is a heterogenic clinical syndrome with a multifactorial etiology including diverse environmental, immunological and genetic causes and modifiers. Increasingly, utilizing next generation sequencing tooIs, monogenic forms of SLE have been identified.ObjectivesThe aim of our study was to identify monogenic causes of SLE in the unique pediatric population of Northern Israel.MethodsA retrospective and prospective study was carried out between 2010-2021 in a single tertiary pediatric medical center. Genetic testing including Whole exome sequencing (WES) was performed for select patients including family history of SLE, consanguinity and\or clinical findings suggestive of specific disorder.Results75 children were diagnosed with SLE. 13/75 had one or more relatives with SLE, including a pedigree with 4 affected members. Mean age at presentation was 10.1±4.7. A monogenic disorder was identified in total of 7/75 of pedigrees. Four patients were dia...
Pediatric Infectious Disease Journal, May 26, 2020
Pediatric inflammatory multisystem syndromes associated with Severe Acute Respiratory Syndrome Co... more Pediatric inflammatory multisystem syndromes associated with Severe Acute Respiratory Syndrome Coronavirus 2 are emerging in recent reports. We describe a patient with critical illness consistent with atypical Kawasaki disease with cardiac dysfunction and abdominal involvement presenting weeks after Severe Acute Respiratory Syndrome Coronavirus 2 infection. Our patient showed unique central nervous system involvement with small vessel vasculitis and profound hypocomplementemia, both not previously reported in case descriptions and may hint at possible disease mechanisms.
Objectives Takayasu arteritis (TAK) is a large-vessel vasculitis rarely reported in children and ... more Objectives Takayasu arteritis (TAK) is a large-vessel vasculitis rarely reported in children and infants. Most articles on paediatric TAK have not focused on infants. We present the largest case series of infantile TAK, aiming to identify its demographic and clinical characteristics and compare them with existing data on older children. Methods We conducted an international multicentre retrospective cohort study. Epidemiological and clinical data were collected from patients’ charts from six rheumatology centres. All patients met both the EULAR/PReS 2008 criteria and the 1990 ACR/EULAR criteria and were diagnosed with TAK at age &lt;5 years. Results Twelve patients were included (50% female). Median age of symptom onset was 11 months, with a diagnostic delay of 4 months. The most common symptoms at presentation were hypertension, blood pressure differences between limbs, and fever. The most commonly involved arteries were the abdominal aorta and renal artery. Medications included steroids, conventional and biologic DMARDs, and other immunosuppressive therapies. Half of the patients received biologic agents, of which infliximab had the highest complete remission rate (40%). Other medications resulting in complete remission were CYC (40%) and MTX (38%). Invasive procedures were required for 58% of patients. The most common complications were cardiac (50%), stroke (42%), and serious infections (33%). No patients died. Conclusion This study presents the largest series of infantile TAK. Compared with other reported series on older children, infants with TAK have more severe disease and were more likely to receive biologic agents, develop complications, and require invasive interventions.
Background Familial Mediterranean fever (FMF) is the most common hereditary autoinflammatory synd... more Background Familial Mediterranean fever (FMF) is the most common hereditary autoinflammatory syndrome, affecting > 100,000 people. FMF is caused by mutations in the MEFV gene, which encodes for the pyrin protein that is part of the inflammation complex that activates IL-1β. Evidence from case reports/series and one controlled study support IL-1 blockage as a potential treatment for FMF. Canakinumab (CAN) is a selective fully human monoclonal anti-IL-1β antibody approved in the EU and US for the treatment of cryopyrin associated periodic syndrome (CAPS). Objectives This study served as a proof of concept to evaluate the role of CAN in the treatment of pediatric colchicine resistant (CR)-FMF. Methods This was a 2-center open-label, single-arm study. The population consisted of CR FMF patients (pts) 4-20 years of age, with a history of at least 3 documented FMF attacks in the 3 months prior to enrollment. Pts entered a 30-day run-in period (RI) during which FMF attacks were documented in a diary. Pts who experienced an investigator-confirmed FMF attack during RI were eligible to enter the treatment phase and receive a SC injection of CAN 2 mg/kg (max 150 mg) every 4 weeks for three times with the 1st dose given during an attack. The dose was doubled to 4 mg/kg (max 300 mg) if an attack occurred between Day 1 Baseline and Day 29 visits. Following the end of the treatment period, pts were followed until day 144 or until an attack occurred, whichever occurred first. Primary outcome was the proportion of pts with ≥50% reduction in FMF attack rate during the treatment vs. pretreatment period. Results Fifteen Israeli pts (9 males, 6 females) entered the RI period and 7 (median age 9.5 yrs; 6.8-14.9 yrs) all with CR FMF advanced to the treatment period. In total, 6/7 (86%) pts had a ≥50% reduction in their FMF attack rate during the treatment period. The median attack rate prior to CAN was 2.7 per 28 days, this decreased to 0.3 per 28 days during treatment, representing a median 89% reduction. Five mild and 3 moderate attacks were experienced by 4 pts (1 with 4 attacks, 1 with 2 attacks and 2 with 1 attack) during the treatment period; 2 pts had their CAN dose uptitrated. Investigators rated FMF control as very poor (n=3), poor (n=3) or fair (n=1) at baseline; this improved to good (n=3) /very good (n=4) for all pts during the treatment period. Elevated median baseline CRP and SAA normalized by Day 8, ESR by Day 28 and all remained normal for remainder of trial. Only 5/7 pts experienced an attack during follow up; the median time to attack following the last CAN dose was 25 days (3-34 days). In all, 11 adverse events (AEs) in 4 pts were reported after the first CAN dose; all were mild except for 2 moderate AEs (Strep infection, laceration), none led to medication discontinuation. Conclusions In this study of pediatric pts with colchicine resistant FMF, Canakinumab every 4 weeks substantially reduced the FMF attack rate consistent with that reported in adults. AEs were manageable. Further study is needed to better define the benefit of Canakinumab in FMF. Disclosure of Interest R. Brik: None Declared, Y. Butbul Aviel: None Declared, S. Lubin Employee of: Novartis, E. Ben Dayan Employee of: Novartis, L. Tseng Employee of: Novartis, P. Hashkes Grant/research support from: Novartis, Consultant for: Novartis, Speakers bureau: Novartis
Objectives: Behçet's disease (BD) is a variable vessel vasculitis. The most widely used classific... more Objectives: Behçet's disease (BD) is a variable vessel vasculitis. The most widely used classification criteria for adults is the International Behçet's Study Group (ISG) criteria. Recently, the paediatric BD (PEDBD) classification criteria has been developed for children. For disease activity, there are mainly two severity scores; the Iranian BD dynamic activity measure (IBDDAM) and BD current activity form (BDCAF). We tested the performances of PEDBD and ISG criteria and the correlation between severity scores and physician global assessment (PGA) in children with BD. Methods: Thirty BD patients from Hacettepe University, Ankara, Turkey; 24 from Erciyes University, Kayseri, Turkey; and 14 BD patients from Rambam Medical Centre, Haifa, Israel were included. As controls, children with systemic lupus erythematosus, polyarteritis nodosa, and Crohn disease from Turkey and Israel were included. The sensitivity and specificity of the PEDBD and ISG criteria were evaluated based on the features of the patients before or at 16 years of age. The gold standard for the diagnosis of BD was based on expert opinion at each centre. Expert PGA (visual analogue scale between 0-10; where 0 indicates no disease activity), IBDDAM, and BDCAF were evaluated at the time of diagnosis and at last follow-up in all patients. Results: Sixty-eight BD (disease onset≤16 years; 44.1% male) and 90 control patients were included. The sensitivity and specificity of PEDBD/ISG criteria were 73.5%/52.9% and 97.7%/100%, respectively. Thirty-two (47%) patients with BD failed to fulfill ISG criteria while almost all met PEDBD criteria. The median (interquartile range; IQR) IBDDAM and BDCAF scores at diagnosis were 6(4)/4(2); significantly decreased to 1(2)/1(2), respectively at latest follow-up (p<0.001 for both). The median (IQR) PGA score at diagnosis was 5(2); significantly decreased to 1(2) at latest follow-up (p<0.001). IBDDAM positively correlated with BDCAF (r=0.637; p<0.001). PGA positively correlated with BDCAF and IBDDAM (r=0.502; p<0.001 and r=0.624;p<0.001, respectively). Conclusions: In our study, the PEDBD criteria showed better sensitivity than ISG criteria which is a big advantage for paediatric patients for early diagnosis. We also demonstrated that the severity scores were positively correlated with each other and PGA; thus may be used in clinical practice for paediatric BD patients.
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